EP1077721B1 - Prevention et traitement de l'hypergastrinemie - Google Patents

Prevention et traitement de l'hypergastrinemie Download PDF

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EP1077721B1
EP1077721B1 EP99924258A EP99924258A EP1077721B1 EP 1077721 B1 EP1077721 B1 EP 1077721B1 EP 99924258 A EP99924258 A EP 99924258A EP 99924258 A EP99924258 A EP 99924258A EP 1077721 B1 EP1077721 B1 EP 1077721B1
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gastrin
glu
use according
hypergastrinemia
pro
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EP1077721A4 (fr
EP1077721B8 (fr
EP1077721A1 (fr
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Philip C. Gevas
Stephen Grimes
Stephen Karr
Dov Michaeli
Susan Watson
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Receptor Biologix Inc
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Receptor Biologix Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/26—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against hormones ; against hormone releasing or inhibiting factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2207—Gastrins; Cholecystokinins [CCK]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/643—Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/595—Gastrins; Cholecystokinins [CCK]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues

Definitions

  • the invention relates to the prevention and/or treatment of hypergastrinemia by immunological control of gastrin levels.
  • hypergastrinemia In humans, treatment with proton pump inhibitors, infection with Helicobacter pylori and pernicious anemia account for the majority of cases of hypergastrinemia. Marked hypergastrinemia is seen in the relatively infrequent Zollinger-Ellison Syndrome (ZES).
  • ZES Zollinger-Ellison Syndrome
  • One of the direct effects of hypergastrinemia is, of course, high secretion rates of gastric acid in the stomach.
  • PA pernicious anemia
  • Gastrin peptides are the products of extensive post-translational processing as outlined in Fig. 1.
  • the first translation product of a single mRNA of 0.7 kb is the 101 amino acid precursor preprogastrin. This peptide is translocated into the lumen of the rough endoplasmic reticulum where it is converted into the progastrin peptide.
  • the progastrin moves through the secretory pathway to the golgi stack, and is sulfated at Tyr 87 prior to endoproteolytic cleavage and maturation in the secretory granules.
  • progastrin is processed to give G34 from dibasic cleavage at sites Arg 57 Arg 58 and Arg 94 Arg 95 and to give G17 from dibasic cleavage at sites Lys 74 Lys 75 and Arg 94 Arg 95 .
  • prehormone convertase 2 (PC2) producing G17 is located primarily in the gastric antrum
  • prohormone convertases PC I/PC3 producing G34 are located in the duodenum.
  • the dibasic cleavage residues are removed by carboxypeptidase H (CPH) producing Gly 93 extended gastrins serving as substrates for the amidation enzyme, PAM (peptidylglycine ⁇ -amidating monoxgenase).
  • G17 gastrin appears to be a conversion product of G34 NH 4 which is an amidation product of Gly-G34.
  • Gly G17 has been thought as a second endpoint of progastrin processing.
  • Gastrin effects on tumor cells are via endocrine, paracrine, autocrine and intracrine pathways (Fig. 2) where, however, not all receptor types have been characterized. It is known that exogenous gastrin stimulates gastric and colorectal tumor cells and tumor cell lines.
  • ECL enterochromaffin-like
  • omeprazole Long-term treatment with omeprazole is known to induce ECL cell hyperplasia which is related to the serum gastrin level.
  • Chronic hypergastrinemia-related carcinoid tumors of the stomach have been reported in certain animals test subjects, e.g. rats, although not yet confirmed in the human [Sobhani et al, Gastroenterology , 105 :22-30 (1993)].
  • Proton pump inhibitors cause a twofold to fourfold increase in fasting and postprandial plasma gastrin concentrations.
  • the increase in fasting hypergastrinemia occurs within a few months of starting therapy.
  • markedly elevated gastrin levels (10 fold) may develop during long term treatment with omeprazole, e.g., 20-60mg/day.
  • Gastrin levels stabilize after a few months of therapy even if the dose of omeprazole is decreased from 40mg to 20 mg daily [Sontag et al, Gastroenterology , 102 :109-118 (1992)].
  • ECL hyperplasia in animal models occurs following the administration of omeprazole.
  • the relative growth of both exocrine and endocrine cells produced by hypergastrinemia varies between species.
  • administration of omeprazole, (400 ⁇ mol/kg, 14mg/kg) to mice for 10 weeks resulted in a threefold increase in plasma gastrin during treatment.
  • the stomach weight increased by 34% and the ECL density by 37% at the end of treatment.
  • the same dose has been found in rats to increase the gastrin levels 10-fold, resulting in the same general trophic effect (increase of stomach and mucosal weight) as in mice, but the ECL cell density increases by about 300%.
  • the significance of this imbalance in the trophic effect of gastrin on the exocrine cells and ECL cells for the development of carcinoids in rats is not known.
  • TGF- ⁇ transforming growth factor alpha
  • gastrin autocrine pathway potentially acts in a co-operative way with the gastrin autocrine pathway [Howell et al, J.Call. Physiol.(1995), 162(2):256-265]
  • the lack of response of the carcinoids to exogenous gastrin may reflect the increasing activity of the gastrin autocrine pathway.
  • the gastrin gene is apparently activated to rather a lower extent in adenomas than adenocarcinomas.
  • gastrin acts as a mitogen, and thus would not be expected to cause a cell to mutate.
  • This hypothesis which has been confirmed in transgenic hGAS mouse studies.
  • the mucosa has an enhanced proliferation rate, there may be an increased chance of sporadic mutation.
  • the only example of malignant change in animal models occurring in the presence of hypergastrinemia is carcinoid in rats following long term omeprazole administration. Although this finding is particular to rats, and no other animal model produces spontaneous carcinoids, it was felt that omeprazole may have a direct carcinogenic effect.
  • exogenous gastrin can continue to promote growth. This effect may be enhanced by gastrin/CCKB receptors which are expressed de novo on adenomas.
  • gastrin/CCKB receptors which are expressed de novo on adenomas.
  • the exact point in the adenoma-carcinoma transformation sequence at which the gastrin/CCKB receptor and autocrine gastrin are expressed is not yet known. Hypergastrinemia may increase this transforming progression through the stages of the adenoma-carcinoma sequence.
  • a therapeutic method for selectively immunologically neutralizing the biological activity of the gastrin hormone would provide an effective means to control or prevent the physiopathological changes resulting from hypergastrinemia.
  • immunogenic constructs of this invention include an aminoterminal (1-9) G17 peptide or an aminoterminal (1-6) G34 pentide conjugated via a peptide spacer to an immuogenic carrier.
  • the preferred G17 sequence is pyro-Glu-Gly-Pro-Trp-Leu-Glu-Glu-Glu [SEQ ID NO: 1] and the preferred G34 sequence is pGlu-Leu-Gly-Pro-Gln-Gly-Arg-Pro-Pro-Pro-Pro-Cys [SEQ ID NO: 2].
  • the preferred spacer in both constructs is a Ser-peptide (Ser-Ser-Pro-Pro-Pro-Pro-Pro-Cys [SEQ ID NO: 3]).
  • the preferred immunogenic carrier is diphtheria toxoid, tetanus toxoid, keylimpet hemocyanin, and bovine serum albumin (BSA).
  • the gastrin immunogen is defined as a conjugate of the pGlu- Gly-Pro-Trp-Leu-Glu-Glu-Glu-Glu [SEQ ID NO: 1] peptide sequence, with an amino acid spacer linked to an immunogenic carrier.
  • the preferred gastrin immunogen is defined as a conjugate of the (1-9) amino terminal (pGlu-Gly-Pro-Trp-Leu-Glu-Glu-Glu-Glu [SEQ ID NO: 1]) peptide which is linked by peptide spacer to diphtheria toxoid. It is further known that the gastrin immunogen preparation is also effective for inhibiting the incompletely processed or progastrin type gastrin precursors which may be bound to the cell membrane of a gastrin producing cell.
  • compositions and methods to effectively treat hypergastrinemia There is a need in the art for compositions and methods to effectively treat hypergastrinemia.
  • the present invention is directed to the treatment for control or prevention of gastrointestinal disorders such as hypergastrinemia by administering a gastrin immunogen preparation to an afflicted mammal or human. Accordingly the invention is as defined in the claims which follow.
  • a preferred embodiment of the treatment is directed to the control or prevention of hypergastrinemia due to pernicious anemia.
  • Another preferred embodiment of this invention is directed to the treatment for control or prevention of gastrointestinal side effects due to antiulcer agents such as proton pump inhibitors or histamine H 2 receptor blocking agents or antagonists.
  • gastrin immunogen against gastrin peptide G17, G34, amidated gastrin and progastrin.
  • the anti-G17 immunogen as described in U. S. Patent Nos. 5,609,870; 5,468,494; 5,785,970 and in the co-assigned patent application 08/798,423 has been found to provide an effective agent to stimulate anti-G17 antibodies-which cross-react with Gly extended G17 (G17-Gly), amidated G17 (G17 NH 2 ) so as to be suitable for treating gastrointestinal tumors which are responsive to these gastrin peptides.
  • Gly G17 and G17 NH 2 can be neutralized with an anti-G17 immunogen composition, such as G17 (1-9) Ser DT, while G34 can be neutralized with anti-G34 (1-17) immunogens.
  • G17 and G34 can be neutralized by anti-G34 (13-22) and anti-G34 (17-31) immunogens which generate antibodies able to cross-react with both gastrin epitopes.
  • Passive immunization can be effected by the specific antibodies generated by immunogens against the various G17 and G34 epitope. These antibodies will either react specifically and separately with the G17 or G34 epitopes or react with both such gastrin epitopes together.
  • a further embodiment provides passive immunization with anti-G17 antibodies which may be humanized to treat hypergastrinemia.
  • a perfected combination treatment of hypergastrinemia and concomitant excess product of gastric acid involves administration of proton inhibitors or H 2 histamine receptor blockers.
  • immunogenic constructs useful in this invention include an aminoterminal (1-9) G17 peptide or an aminoterminal (1-6) G34 peptide conjugated via a peptide spacer to an immunogenic carrier.
  • the preferred G17 sequence is pyro-Glu-Gly-Pro-Trp-Leu-Glu-Glu-Glu [SEQ ID NO: 1] and the preferred G34 sequence is pGlu-Leu-Gly-Pro-Gln-Gly-Arg-Pro-Pro-Pro-Pro-Cys [SEQ ID NO: 2]
  • the preferred spacer in both constructs is a Ser-peptide (Ser-Ser-Pro-Pro-Pro-Pro-Cys [SEQ ID NO: 3]).
  • the preferred immunogenic carrier is diphtheria toxoid, tetanus toxoid, keylimpet hemocyanin, and bovine serum albumin (BSA).
  • the gastrin immunogen is defined as a conjugate of the pGlu- Gly-Pro-Trp-Leu-Glu-Glu-Glu-Glu [SEQ ID NO: 1] peptide sequence, with an amino acid spacer linked to an immunogenic carrier.
  • the preferred gastrin immunogen is defined as a conjugate of the (1-9) amino terminal (pGlu-Gly-Pro-Trp-Leu-Glu-Glu-Glu-Glu [SEQ ID NO: 1]) peptide which is linked by peptide spacer to diphtheria toxoid.
  • one of the generating antibodies binding to both G17 and G34 comprises a conjugate of the 7 amino acids of C-terminal G17 amino acid sequence 11-17-DT.
  • This sequence is E-A-Y-G-W-M-D-NH 2 [SEQ ID NO: 4].
  • Min mice In order to explore whether gastrin may promote progression to malignancy in existing pre-malignant conditions, studies were undertaken, for example, in the multiple intestinal neoplasia or so-called Min mouse model of familial adenomatous polyposis (FAP).
  • FAP familial adenomatous polyposis
  • the mice have a germline mutation in their APC gene which leads to multiple intestinal neoplasia.
  • Hypergastrinemia which was induced by use of the proton pump inhibitor, omeprazole, has been now found to increase progression to malignancy in Min mice, reducing their median survival from approximately 10 weeks to 6 weeks. Examination of the proliferation of tumors from Min mice exposed to elevated gastrin levels revealed by bromodeoxyuridine incorporation that proliferation was increased.
  • gastrin gene In addition to the proliferative effects of serum-associated gastrin, acting in an endocrine manner to increase proliferation, expression of the gastrin gene has also been shown in the colonic mucosa in pre-malignant condition.
  • the gastrin gene In the transgenic APC1628 mouse, the gastrin gene is activated in both the normal colonic mucosa and the malignant epithelium [Smith et al, Brit J.Surg. , 84 :706 (1997)]. This has recently been confirmed by applicants by both immunocytochemistry and at the gene level in the Min mouse. In addition, activation of the gastrin gene has been found in human adenomas [Smith et al, (1997) cited above]. Thus, a gastrin-mediated autocrine/paracrine way may also be operational in the pre-malignant scenario.
  • Min mice used in the study were bred within the Academic Unit of Cancer Studies at Nottingham University (U.K.) on a C57/BL background. As the homozygous state is lethal and female Min mice do not lactate; a Min heterozygote is bred with a female wild type and 1:4 offspring have the Min genotype. The Min positive mice were then placed into each arm of the therapy on an ongoing basis.
  • the immunization with hG17-DT immunogen (G-17 conjugate) (Fig. 3), is effective in neutralizing circulatory gastrin levels as well as tissue bound precursors or incompletely processed progastrin.
  • exogenous anti-G17 antibodies which can be in humanized form
  • a patient can be preimmunized against hypergastrinemia or hypergastrinemic effects caused by treatment with proton inhibitors (omeprazole, lansoprazole, or pantoprazole) or H 2 receptor blockers (ranitidine, cimetidine, formatidine or nizatidine).
  • proton inhibitors omeprazole, lansoprazole, or pantoprazole
  • H 2 receptor blockers ranitidine, cimetidine, formatidine or nizatidine.
  • Humanized antibodies may be prepared by techniques known in the art.
  • the hG17-DT conjugated immunogen or method of preparation are disclosed in U.S. Patent No. 5,609,870, U.S. Patent No. 5,468,494 and U.S. Patent No. 5,023,077. See, also, Examples 3 and 4 below.
  • the endpoint of the treatment which has previously been validated by Moser et al. (1990), is at the terminal stage of the disease, when the mice have a large tumor burden, blood is lost in the stools, and the animals become anemic.
  • Gastrin neutralization was achieved by using an immunogen, i.e. the gastrin immunogen preparation, which is composed of the amino terminal domain of gastrin-17 linked, via an amino acid spacer, to diphtheria toxoid which acts as the immunogenic carrier.
  • the antibodies raised by virtue of the design of the immunogen cross-react with both amidated and glycine-extended gastrin-17, known proliferative forms of gastrin.
  • Min mice were immunized s.c. with the hG17-DT immunogen (100 mg/mouse) at week 4, with subsequent injections at 3 weekly intervals. Serum antibody titres are known to rise within 2 weeks of the first immunization at levels with an antigen binding capacity of > 10 -9 M.
  • the hG17-DT immunogen was administered to mice at 4 weeks of age to examine its effect on mice with an established tumor burden. Control mice received immunogen constituents without the active peptide.
  • Bound gastrin levels were not measurable in animals immunized with control immunogen.
  • the bound gastrin levels in the gastrin immunogen-immunized mice were 37pg/ml.
  • the bound gastrin levels was 148.3pg/ml which highlights the capacity of the antibodies raised in the serum for gastrin neutralization (Fig. 4).
  • mice were injected with DNA analogue bromodeoxyuridine in order to determine the comparative in situ proliferation activity.
  • the samples were formalin fixed, paraffin embedded, sections were cut and stained with an anti-bromodeoxyuridine antibody.
  • Fig. 6 There was no significant difference in the proliferation of crypts from both the small and large intestine due to gastrin immunogen treatment (Fig. 6).
  • the proliferation of the small intestinal tumors were significantly inhibited by 19.8%, as was the proliferation of the large intestinal tumors which was inhibited by 41 %.
  • the normal colonic mucosa is sensitive to the proliferative effects of hypergastrinemia involving both amidated gastrin and progastrin (Wang, et al., 1997; Renga et al., 1997).
  • APC1638 and Min mice both have mutations in their APC gene) have an activated gastrin gene in both normal and malignant colonic mucosa, unlike the corresponding wild type mice.
  • Min mice have greater proliferation levels in normal mucosa when compared to the wild type C57/BL mouse.
  • Hypergastrinemia induced by treatment with high daily doses of omeprazole decreases the survival of Min mice, which is partially reversed when co-administered with gastrin immunogen. There is an initial 2 week window when hypergastrinemia is unopposed due to lack of anti-gastrin antibodies. This effect is completely reversed when omeprazole treatment is delayed for 2. weeks allowing anti-gastrin antibody titers to rise prior to onset of hypergastrinemia.
  • the Min mouse anti-G17(1-9):DT antibody data are illustrated in Fig. 8. Measurement of the free and bound serum carboxy-amidated gastrin levels in immunized animals revealed a mean free gastrin level of 28.9pg/ml and a bound level of 36.7pg/ml (Fig. 9).
  • the Min mouse serum G17 data are illustrated in Fig. 9. The data are shown in Table 1.
  • Min + genotype mice were randomized into 4 groups:
  • Serum gastrin level was measured by RIA. Prior to end of treatment, proliferative index was determined by the bromodeoxyuridine method.
  • the hypergastrinemic mice had enhanced proliferation of normal colonic mucosa. It was found that 9.46% proliferating cells increased to 20.1%, p ⁇ 0.05, Mann-Whitney and colonic neoplasia (22.3% increased 35.0%, p ⁇ 0.01). Thus, the level of this experimental hypergastrinemia was in the range attained in the humans on a maintenance dose of omeprazole and resulted in enhanced progression through the adenoma:carcinoma sequence. Moreover, gastrin was confirmed as the mediator inducing a state of hyper-proliferation within both normal and neoplastic colonic epithelium. This data demonstrate the need and effectiveness for controlling hypergastrinemia on pre-malignant colon by gastrin immunogen immunization.
  • Polypoid carcinomas have been established in vitro from the large and small intestine of Min mice. Proliferation was assessed by a tetrazolium-based colorimetric ELISA assay. It was found that proliferation of both tumor types was not increased by amidated gastrin, but the large intestinal tumor was modestly stimulated by glycine-extended gastrin.
  • Gastrin immunogen immunization significantly affects the survival of Min mice when administered early in their life span. Moreover, the proliferation index of tumors in the large intestine was more extensively inhibited by the G17-DT immunogen than that of tumors arising in the small intestine. In this context, tumors from the large intestine of Min mice appear to be more sensitive to the proliferative effects of GlyG17 than tumors from the small intestine. This could be both serum-associated and tumor-associated GlyG17, the latter being due to activation of the gastrin gene in these tumors.
  • Treatment with the G17-DT immunogen as described is useful in reversing hyper-gastrinemic states induced by a variety of conditions, including, PA, H. pylori, atrophic gastritis, total or partial gastrectomy, treatment with proton pump inhibitors or H 2 blockers.
  • the G17-DT immunogen is potentially effective in protecting the subject mammal, including humans, from induction of cancers responsive to gastrin (colon, stomach, pancreas, and liver).
  • Immunization against gastrin induces an effective immune response in humans such that it reduces serum gastrin levels in hypergastrinemic patients to normal or lower levels.
  • Treatment of PA patients exhibiting hypergastrinemia with immunization (active or passive) against gastrin can be applied alone or in combination with a secondary step of anti-gastric acid administration proton pump inhibitors such as omeprazole or lansoprazole, as well as H 2 receptor blocking agents, such as rantidine cimetidine, fomatidine or nizatidine.
  • proton pump inhibitors such as omeprazole or lansoprazole
  • H 2 receptor blocking agents such as rantidine cimetidine, fomatidine or nizatidine.
  • Immunogens capable of inducing specific immune responses to either G17 or to G34 were prepared by standard solid state synthesis methods. Each peptide was characterized as to amino acid content and purity.
  • Each of these peptides were conjugated to amino groups present on a carrier such as Diphtheria toxoid ("DT") via the terminal peptide cysteine residue utilizing heterobifunctional linking agents containing a succinimidyl ester at one end and maleimide at the other end of the linking agent.
  • DT Diphtheria toxoid
  • the dry peptide was dissolved in 0.1 M Sodium Phosphate Buffer, pH 8.0, with a thirty molar excess of dithiothreitol ("DTT"). The solution was stirred under a water saturated nitrogen gas atmosphere for four hours. The peptide containing reduced cysteine was separated from the other components by chromatography over a G10 Sephadex column equilibrated with 0.2 M Acetic acid. The peptide was lyophilized and stored under vacuum until used.
  • DTT dithiothreitol
  • the carrier was activated by treatment with the heterobifunctional linking agent, e.g., Epsilon-maleimidocaproic acid N-hydroxysuccinimide ester, ("EMCS"), in proportions sufficient to achieve activation of approximately 25 free amino groups per 10 5 molecular weight of carrier.
  • EMCS Epsilon-maleimidocaproic acid N-hydroxysuccinimide ester
  • diphtheria toxoid Activation of diphtheria toxoid was accomplished by dissolving each 20 mg aliquot of diphtheria toxoid in 1 ml of 0.2 M Sodium Phosphate Buffer, pH 6.45. Aliquots of 6.18 mg EMCS were dissolved into 0.2 ml of Dimethyl Formamide ("DMF"). Under darkened conditions, the EMCS was added dropwise in 50 microliter (“ul”) amounts to the DT with stirring. After 2 hours of incubation in darkness, the mixture was chromatographed on a G50 Sephadex column equilibrated with 0.1 M Sodium Citrate buffer, pH 6.0, containing 0.1 mM EDTA.
  • DMF Dimethyl Formamide
  • Fractions containing the EMCS activated diphtheria toxoid were concentrated over a PM 10 ultrafiltration membrane under conditions of darkness.
  • the protein content of the concentrate was determined by either the Lowry or Bradford methods.
  • the EMCS content of the carrier was determined by incubation of the activated carrier with cysteine-HCI followed by reaction with 10 mM of Elman's Reagent 5,5'dithio-bis (2-nitrobenzoic acid) 10 mM.
  • the optical density difference between a blank tube containing cysteine-HCl and the sample tube containing cysteine-HCl and carrier was translated into EMCS group content by using the molar extinction coefficient of 13.6 x 10 3 for 5-thio-2-nitro benzoic acid at 412 nm.
  • the reduced cysteine content (-SH) of the peptide was also determined utilizing Elman's Reagent. Approximately 1 mg of peptide was dissolved in 1 ml of nitrogen gas saturated water and a 0.1 ml aliquot of this solution was reacted with Elman's Reagent. Utilizing the molar extinction coefficient of 5-thio-2-nitro-benzoic acid (13.6 x 10 3 ), the free cysteine -SH was calculated. An amount of peptide containing sufficient free -SH to react with each of the 25 EMCs activated amino groups on the carrier was dissolved in 0.1 M Sodium Citrate Buffer, pH 6.0, containing 0.1 mM EDTA, and added dropwise to the EMCS activated carrier under darkened conditions. After all the peptide solution had been added to the carrier, the mixture was incubated overnight in the dark under a water saturated nitrogen gas atmosphere.
  • the conjugate of the peptide linked to the carrier via EMCS is separated from other components of the mixture by chromatography over a G50 Sephadex column equilibrated with 0.2 M Ammonium Bicarbonate.
  • the conjugate eluted in the column void volume is lyophilized and stored desiccated at 20°C until used.
  • the conjugate may be characterized as to peptide content by a number of methods known to those skilled in the art including weight gain, amino acid analysis, etc. Conjugates of these peptides and diphtheria toxoid produced by these methods were determined to have 20-25 moles of peptide per 10 5 MW of carrier and all were considered suitable as immunogens for immunization of test animals.
  • Peptide hG17(1-9)-Ser9 was prepared by standard solid state synthesis methods. That peptide contains an amino terminal immunomimic of hG17 followed by a carboxy terminal spacer. This peptide comprises a 9 amino acid immunomimic of hG17 (pGlu-Gly-Pro-Trp-Leu-Glu-Glu-Glu-) followed by the "Ser" spacer (-Ser-Ser-Pro-Pro-Pro-Pro-Pro-Cys) attached to amino acid number 9 of the hG17 immunomimic.
  • the peptide was conjugated to amino groups present on the Diphtheria Toxoid ("DT") immunogenic carrier via the terminal peptide cysteine residue utilizing heterobifunctional linking agents containing a succinimidyl ester at one end and maleimide at the other end of the linking agent essentially as described in Example 3.
  • DT Diphtheria Toxoid
  • the immunogenic constructs of this invention include an aminoterminal (1-9) G17 peptide or an aminoterminal (1-6) G34 peptide conjugated via a peptide spacer to an immunogenic carrier.
  • the preferred G17 sequence is pyro-Glu-Gly-Pro-Trp-Leu-Glu-Glu-Glu and the preferred G34 sequence is pGlu-Leu-Gly-Pro-Gln-Gly-Arg-Pro-Pro-Pro-Pro-Pro-Cys.
  • the preferred spacer in both constructs is a Ser-peptide (Ser-Ser-Pro-Pro-Pro-Pro-Cys).
  • the preferred immunogenic carrier is diphtheria toxoid, tetanus toxoid, keylimpet hemocyanin, and bovine serum albumin (BSA).
  • the gastrin immunogen is defined as a conjugate of the pGlu- Gly-Pro-Trp-Leu-Glu-Glu-Glu peptide sequence, with an amino acid spacer linked to an immunogenic carrier.
  • the preferred gastrin immunogen is defined as a conjugate of the (1-9) amino terminal (pGlu-Gly-Pro-Trp-Leu-Glu-Glu-Glu-Glu) peptide which is linked by peptide spacer to diphtheria toxoid.
  • Antisera were absorbed onto a solid phase at a concentration of 100 ⁇ g/ml and displacement was determined in a competitive assay with a fixed concentration of radiolabelled G17 (100 pg/ml) and increasing concentrations of unlabelled ligands (I-25,000 pg/ml).
  • Figs. 11 and 12 show the displacement of [ 125 I]G17 from rabbit anti-human G17 antiserum by G17, G17-Gly and G34.
  • the antiserum used in the test depicted in Fig. 11 was obtained form animals immunized with G17(1-9):DT and was specific for the N-terminal end of G17; the antiserum for Fig. 12 was specific for the C-terminal end of G17.
  • IC 50 50% inhibitory concentration
  • Glycine-extended G17 did not displace radiolabelled G17 from the C-terminal specific antiserum, but did from the N-terminal specific antiserum (IC 25 12,000 pg/ml), demonstrating that the glycine-extended G17 binds to N-terminal specific antiserum, but not to C-terminal specific antiserum.
  • G34 displaced radiolabelled G17 from the C-terminal (IC 25 500 pg/ml), but not the N-terminal specific antiserum, demonstrating the specificity of the G17(1-9):DT antiserum for G17 and glycine-extended G17 and not to G34.

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Claims (14)

  1. Utilisation (i) d'une composition immunogène comprenant un peptide G17 de pGlu-Gly-Pro-Trp-Leu-Glu-Glu-Glu-Glu- ; et (ii) d'un agent anti-ulcéreux choisi dans le groupe constitué par un bloquant du récepteur de l'histamine et un inhibiteur de la pompe à protons, pour la préparation d'un médicament pour le traitement d'hypergastrinémie dans un mammifère.
  2. Utilisation selon la revendication 1, où ladite hypergastrinémie est associée à
    a) une condition choisie dans le groupe constitué par l'anémie pernicieuse, une tumeur gastrique, un cancer gastrique, ou
    b) un traitement thérapeutique avec une substance qui résulte dans des niveaux augmentés de gastrine.
  3. Utilisation selon la revendication 1 ou 2, où ledit peptide est conjugué à un vecteur immunogène.
  4. Utilisation selon la revendication 1 ou 2, où ledit peptide G17 de pGlu-Gly-Pro-Trp-Leu-Glu-Glu-Glu-Glu- est lié au moyen d'un espaceur en acides aminés à un vecteur immunogène.
  5. Utilisation selon la revendication 4, où ledit vecteur immunogène est choisi dans le groupe constitué par le toxoïde de la diphtérie, le toxoïde du tétanos et l'hémocyanine de patelle.
  6. Utilisation selon la revendication 1, où ladite composition (i) induit des anticorps anti-gastrine qui se lient à 1a gastrine.
  7. Utilisation selon la revendication 6, où lesdits anticorps se lie à l'heptadécagastrine G17.
  8. Utilisation selon la revendication 1, où ledit bloquant est choisi dans le groupe constitué par la ranitidine, la cimétidine, la famotidine et la nizatidine.
  9. Utilisation selon la revendication 1, où ledit inhibiteur est choisi dans le groupe constitué par l'oméprazole, le lansoprazole et le pantoprazole.
  10. Utilisation selon la revendication 8 ou 9, où ladite composition immunogène est administrée audit mammifère avant ledit agent.
  11. Utilisation selon 1a revendication 8 ou 9, où ladite composition et ledit agent sont co-administrés audit mammifère.
  12. Utilisation selon la revendication 1, où ladite hypergastrinémie est un effet secondaire dudit agent anti-ulcéreux.
  13. Utilisation selon la revendication 1, où lesdits niveaux de gastrine sérique dudit mammifère sont maintenus à un niveau normal.
  14. Utilisation selon la revendication 13, où ladite production d'acide gastrique dudit mammifère est inhibée.
EP99924258A 1998-05-15 1999-05-14 Prevention et traitement de l'hypergastrinemie Expired - Lifetime EP1077721B8 (fr)

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WO1999059631A1 (fr) 1999-11-25
US20050187152A1 (en) 2005-08-25
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JP2002515458A (ja) 2002-05-28
DE69935977T2 (de) 2008-01-10
PT1077721E (pt) 2007-06-21
ES2286883T3 (es) 2007-12-01
ATE361098T1 (de) 2007-05-15
AU4080399A (en) 1999-12-06
DK1077721T3 (da) 2007-09-03
EP1077721A1 (fr) 2001-02-28
CA2328501A1 (fr) 1999-11-25
DE69935977D1 (de) 2007-06-14

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